Reexamining Alzheimer’s disease: Evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. Journal of Alzheimer’s Disease, 18(2), 447-452

Department of Pathology, University of Maryland, Baltimore, MD 21201, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 08/2009; 18(2):447-52. DOI: 10.3233/JAD-2009-1151
Source: PubMed


Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.

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    • "In understanding the role of Aβ in the pathogenesis of AD, two important questions remain unanswered: 1) what are the triggering mechanisms that primarily induce Aβ deposition? and 2) why does Aβ relentlessly accumulate in such a destructive manner? The first question has not been fully addressed, although some interesting hypotheses have been advanced [116], [117], [154]–[157]. In relation to the second, recent data suggest that Aβ deposits self-propagate through the continuous accretion of misfolded and degradation-resistant molecules [108], [158]. "
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    • "The amyloid hypothesis has been the predominant theory of AD etiology for the past two decades (Hardy and Selkoe, 2002). Doubts have surfaced concerning whether Aβ is the ultimate cause of AD in humans (Lee et al., 2004; Castellani et al., 2009; Mullane and Williams, 2013; Roher et al., 2013; Tayeb et al., 2013), but recent neuropathological research shows that individuals who have high levels of Aβ postmortem, but do not have soluble forms of Aβ localized to synapses, did not have prior cognitive impairment (Bjorklund et al., 2012). This finding is consistent with the results of studies on non-human animals showing that high Aβ levels cause abnormalities in synaptic plasticity. "
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